Correlative proteomics identify the key roles of stress tolerance strategies in Acinetobacter baumannii in response to polymyxin and human macrophages

Zhi Ying Kho, Mohammad A.K. Azad, Mei-Ling Han, Yan Zhu, Cheng Huang, Ralf B. Schittenhelm, Thomas Naderer, Tony Velkov, Joel Selkrig, Qi Tony Zhou, Jian Li

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6 Citations (Scopus)

Abstract

The opportunistic pathogen Acinetobacter baumannii possesses stress tolerance strategies against host innate immunity and antibiotic killing. However, how the host-pathogen-antibiotic interaction affects the overall molecular regulation of bacterial pathogenesis and host response remains unexplored. Here, we simultaneously investigate proteomic changes in A. baumannii and macrophages following infection in the absence or presence of the polymyxins. We discover that macrophages and polymyxins exhibit complementary effects to disarm several stress tolerance and survival strategies in A. baumannii, including oxidative stress resistance, copper tolerance, bacterial iron acquisition and stringent response regulation systems. Using the spoT mutant strains, we demonstrate that bacterial cells with defects in stringent response exhibit enhanced susceptibility to polymyxin killing and reduced survival in infected mice, compared to the wild-type strain. Together, our findings highlight that better understanding of host-pathogen-antibiotic interplay is critical for optimization of antibiotic use in patients and the discovery of new antimicrobial strategy to tackle multidrug-resistant bacterial infections.

Original languageEnglish
Pages (from-to)e1010308
Number of pages25
JournalPLoS Pathogens
Volume18
Issue number3
DOIs
Publication statusPublished - 1 Mar 2022

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